Outcome of patients with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcomas enrolled in phase 2 cooperative group clinical trials: A report from the Children's Oncology Group.

BACKGROUND: The aim of this study was to estimate the event-free survival (EFS) of children and young adults with relapsed or refractory nonrhabdomyosarcoma soft tissue sarcoma (NRSTS) treated in nonrandomized phase 2 studies conducted by the Children's Oncology Group (COG) and predecessor groups to establish a benchmark EFS for future phase 2 NRSTS trials evaluating the activity of novel agents. METHODS: A retrospective analysis of patients with recurrent or refractory NRSTS prospectively enrolled in nonrandomized phase 2 COG and predecessor group trials between 1994 and 2015 was conducted. EFS was defined as disease progression/relapse or death and calculated via the Kaplan-Meier method. The log-rank test and relative risk regression were used to compare EFS distribution by age at enrollment, sex, race, NRSTS histology, prior lines of therapy, calendar year of trial, and type of radiographic response. RESULTS: In total, 137 patients were enrolled in 13 phase 2 trials. All trials used radiographic response rate as a primary outcome, and none of the agents used were considered active on the basis of trial-specified thresholds. The estimated median EFS and 6-month EFS of the entire study cohort was 1.5 months (95% confidence interval [CI], 1.3-1.8 months) and 19.4% (95% CI, 12.7%-26%), respectively. No difference in EFS was observed by age at enrollment, sex, race, NRSTS histology subtype, prior lines of therapies, and trial initiation year. EFS significantly differed by radiographic response. CONCLUSIONS: The EFS for children and young adults with relapsed or refractory NRSTS remains suboptimal. Established EFS can be referenced as a benchmark for future single-agent phase 2 trials incorporating potentially active novel agents in this population.

Roadmap for the next generation of Children's Oncology Group rhabdomyosarcoma trials.

Clinical trials conducted by the Intergroup Rhabdomyosarcoma (RMS) Study Group and the Children's Oncology Group have been pivotal to establishing current standards for diagnosis and therapy for RMS. Recent advancements in understanding the biology and clinical behavior of RMS have led to more nuanced approaches to diagnosis, risk stratification, and treatment. The complexities introduced by these advancements, coupled with the rarity of RMS, pose challenges to conducting large-scale phase 3 clinical trials to evaluate new treatment strategies for RMS. Given these challenges, systematic planning of future clinical trials in RMS is paramount to address pertinent questions regarding the therapeutic efficacy of drugs, biomarkers of response, treatment-related toxicity, and patient quality of life. Herein, the authors outline the proposed strategic approach of the Children's Oncology Group Soft Tissue Sarcoma Committee to the next generation of RMS clinical trials, focusing on five themes: improved novel agent identification and preclinical to clinical translation, more efficient trial development and implementation, expanded opportunities for knowledge generation during trials, therapeutic toxicity reduction and quality of life, and patient engagement.

Outcomes for patients with perineal and perianal rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

PURPOSE: To describe clinical features, risk factors, and outcomes of patients with perineal and perianal rhabdomyosarcoma. METHODS: The records of 51 patients (38 perineal and 13 perianal) enrolled on Children's Oncology Group clinical trials between 1997 and 2012 were reviewed. RESULTS: At presentation, 53% were female, 65% were older than 10 years of age, 76% were alveolar histology, 76% were more than 5 cm, 84% were invasive, 65% were regional node positive by imaging, 49% were metastatic, only 16% were grossly resected upfront, and 25% of patients had a delayed excision. At a median follow-up of 6.13 years, estimated 5-year event-free survival (EFS) was 38% [22.17%-53.38%], and overall survival (OS) was 42% [26.66%-58.21%]. The rates of local, regional, and distant failure were 15.6%, 13.7%, 43.1%, respectively; all failures ultimately died. By univariate analysis, only age more than 10 years negatively impacted 5-year EFS (p = .023) and OS (p = .09), and IRS Group also impacted OS (p = .043). In Cox proportional hazards model, neither of these variables were significant after adjusting for other factors. CONCLUSION: Patients with perineal and perianal rhabdomyosarcoma have a poor overall prognosis, probably related to poor patient and disease characteristics at presentation.

Event-free survival in relapsed and refractory rhabdomyosarcoma treated on cooperative group phase II trials: A report from the Children's Oncology Group.

BACKGROUND: Novel therapies are needed for relapsed and refractory rhabdomyosarcoma (RRMS). Phase II clinical trials in RRMS have typically utilized radiologic response as the primary activity endpoint, an approach that poses several limitations in RRMS. In this analysis, we aimed to estimate an event-free survival (EFS) endpoint for RRMS that could be used as a benchmark for future studies. PROCEDURE: We performed a retrospective study of patients with RRMS enrolling on 13 single-agent phase II Children's Oncology Group and legacy group trials from 1997 to 2016. All included trials used radiographic response as their primary activity endpoint. Six-month EFS was estimated from time of trial enrollment with 95% confidence intervals. Clinical characteristics, including trial of enrollment, sex, age, race, histology, number of prior chemotherapies, and radiographic response were evaluated for their impact on 6-month EFS. RESULTS: We identified 175 patients across 13 trials. The 6-month EFS was 16.8% (11.6%-22.8%). No differences were seen in 6-month EFS based on age, sex, race, or histology. There were nonsignificant trends toward improved 6-month EFS for patients with less than or equal to two prior lines of therapy versus higher than two, for patients enrolled on trials that achieved their primary radiographic response endpoint versus trials that did not, and for patients who achieved complete or partial response compared to those achieving stable disease. CONCLUSIONS: The prognosis of RRMS enrolled on single-agent phase II trials is poor. This pooled 6-month EFS of RRMS on single-agent trials may be used as a RRMS-specific benchmark for future single-agent phase II trials.

Outcomes of relapsed favorable-histology Wilms tumor in non-clinical trial setting.

BACKGROUND: The last major North American cooperative group clinical trial for relapsed favorable-histology Wilms tumor (FHWT) was completed in 2002. The outcomes of patients with relapsed Wilms tumor subsequently treated outside of clinical trials are unknown. The aim of this study was to assess the efficacy and toxicity of salvage therapies used for patients with FHWT suffering first relapse. METHODS: We conducted a retrospective chart review of patients treated for first relapse of FHWT at six large North American institutions from January 2002 through August 2018. RESULTS: Ninety-four patients were identified. Thirty-six patients were classified as standard-risk relapse (SRR), 49 patients as high-risk relapse (HRR), and seven patients as very high-risk relapse (VHRR). Two patients were unable to be classified. Twenty-one patients with SRR were treated with Regimen I. The 4-year event-free survival (EFS) and overall survival (OS) for SRR were 82.4% and 93.3%, respectively, with median follow-up of 72 months. Twenty-eight HRR/VHRR patients were treated with ICE therapy, while 13 received National Wilms Tumor Study (5th) (NWTS-5) Stratum C. No patient completed protocol therapy per Stratum C; median maintenance cycles administered were two cycles. The 4-year EFS and OS for HRR/VHRR were 32.6% and 58.3%, respectively, with median follow-up of 33 months. CONCLUSIONS: Outcomes for all strata of relapsed WT patients treated in a non-clinical setting appear to have similar outcomes to historical cohorts treated on NWTS-5. Improved strategies are urgently needed for HRR and VHRR relapses.

Children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Despite bone metastases being present in 5% of patients at diagnosis, there are limited studies examining these outcomes. We sought to define the prognostic factors, clinical courses, and outcomes of children treated on Children's Oncology Group (COG) clinical trials with RMS metastatic to bone at diagnosis. METHODS: We performed a retrospective analysis of patients diagnosed with bone metastatic RMS enrolled on COG RMS clinical trials (D9802, D9803, ARST0431, or ARST08P1) between 1997 and 2013. RESULTS: RMS metastatic to bone was identified in 154 patients at a median age of 14.9 years at diagnosis. Fifty-eight percent of patients were male, 90% had metastases at additional sites, 74% had alveolar histology, and extremity was the most common primary site (31%). Eighty-six percent of patients (n = 133) received radiation therapy. The 3- and 5-year event-free survival (EFS) was 15.4% and 14.5%, respectively. The 3- and 5-year overall survival (OS) was 30.4% and 18.0%, respectively. We identified alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation as poor prognostic characteristics for both EFS and OS in univariate analysis. Lack of radiation was not significant when excluding patients with events prior to 20 weeks. CONCLUSIONS: This study is the largest analysis of patients with bone metastatic RMS, and defines the poor overall outcomes and negative prognostic factors for these patients. They may be eligible for therapy deintensification for improved quality of life or pursuit of novel treatments/approaches, which are desperately needed.

Adolescents and young adults with rhabdomyosarcoma: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

INTRODUCTION: The impact of established prognostic factors on survival outcomes for childhood rhabdomyosarcoma (RMS) have not been well described in the adolescent and young adult (AYA) RMS patient population. METHODS: This is a retrospective analysis of patients with newly diagnosed RMS enrolled between 1997 and 2016 on seven previously reported Children's Oncology Group (COG) clinical trials. Demographics, clinical features, treatment details, and outcome data were collected. Five-year event-free survival (EFS) and overall survival (OS) were estimated for patients diagnosed at age 15-39 years and those diagnosed under age 15 years using the Kaplan-Meier method. Log-rank test was used to compare prognostic factors for EFS and OS. Factors significant in the univariable analysis were included in a Cox proportional hazards regression model. Nonsignificant covariates were removed from the multiple regression model. RESULTS: Total 2151 patients including 402 AYAs were analyzed. AYAs were more likely to present with primary tumors ≥5 cm in size, metastatic disease, alveolar histology, and have FOXO1 fusions compared to children. Five-year EFS for the AYA cohort was 44.2% versus 67% for children (p < .001), and 5-year OS was 52% for the AYA cohort versus 78% for children (p < .001). Multivariable analysis revealed tumor site, size and invasiveness, clinical group, and histology were prognostic in AYAs. CONCLUSION: AYAs with RMS have a poorer prognosis compared to younger children due to multiple factors. Further research focused on AYAs to better understand RMS biology and improve treatments is critical to improve survival.

Survival of patients with orbital and eyelid rhabdomyosarcoma treated on Children's Oncology Group studies from 1997 to 2013: A report from the Children's Oncology Group.

BACKGROUND: Orbital rhabdomyosarcoma (ORMS) commonly presents as low-risk disease (stage 1, group I-III, embryonal RMS) with excellent outcome. Long-term follow-up of patients with low-risk ORMS and outcomes of less common subgroups of ORMS treated on recent Children's Oncology Group (COG) trials have not been reported. METHODS: Patients with ORMS enrolled on COG trials from 1997 to 2013 were identified. Demographic information and disease characteristics were collected. Outcomes were determined for the following subgroups: 1) low-risk ORMS, 2) resected (group I/II) low-risk ORMS, 3) non-low-risk ORMS, and 4) recurrent ORMS. Event-free survival (EFS) and overall survival (OS) were estimated using the Kaplan-Meier method. ResultsThe authors identified 218 patients with ORMS. Most tumors were embryonal/botryoid (n = 169; 77.5%), <5 cm (n = 213; 97.7%), group III (n = 170; 78.0%), and without lymph node involvement (N0; n = 215; 98.6%). For 192 patients with low-risk ORMS, the 10-year EFS and OS rates were 85.5% (95% confidence interval [CI], 77.0%-94.0%) and 95.6% (95% CI, 90.8%-100.0%), respectively. Those with group I/II low-risk ORMS (n = 5 in group I; n = 39 in group IIA) had 10-year EFS and OS rates of 88.0% (95% CI, 72.6%-100.0%) and 97.6% (95% CI, 90.0%-100.0%), respectively. Twenty-six patients with non-low-risk ORMS had 5-year EFS and OS rates of 88.5% (95% CI, 75.6%-100.0%) and 95.8% (95% CI, 87.7%-100.0%), respectively. For patients with recurrent ORMS, the 10-year OS rate from the time of recurrence was 69.4% (95% CI, 50.0%-88.8%). CONCLUSIONS: Patients with ORMS had favorable long-term survival outcomes on COG studies from 1997 to 2013, including those who had both low-risk and non-low-risk disease. A significant proportion of patients with recurrent ORMS may achieve long-term survival.

Deep Learning of Rhabdomyosarcoma Pathology Images for Classification and Survival Outcome Prediction.

Rhabdomyosarcoma (RMS), the most common malignant soft tissue tumor in children, has several histologic subtypes that influence treatment and predict patient outcomes. Assistance with histologic classification for pathologists as well as discovery of optimized predictive biomarkers is needed. A convolutional neural network for RMS histology subtype classification was developed using digitized pathology images from 80 patients collected at time of diagnosis. A subsequent embryonal rhabdomyosarcoma (eRMS) prognostic model was also developed in a cohort of 60 eRMS patients. The RMS classification model reached a performance of an area under the receiver operating curve of 0.94 for alveolar rhabdomyosarcoma and an area under the receiver operating curve of 0.92 for eRMS at slide level in the test data set (n = 192). The eRMS prognosis model separated the patients into predicted high- and low-risk groups with significantly different event-free survival outcome (likelihood ratio test; P = 0.02) in the test data set (n = 136). The predicted risk group is significantly associated with patient event-free survival outcome after adjusting for patient age and sex (predicted high- versus low-risk group hazard ratio, 4.64; 95% CI, 1.05-20.57; P = 0.04). This is the first comprehensive study to develop computational algorithms for subtype classification and prognosis prediction for RMS histopathology images. Such models can aid pathology evaluation and provide additional parameters for risk stratification.

Neoadjuvant pazopanib in nonrhabdomyosarcoma soft tissue sarcomas (ARST1321): A report of major wound complications from the Children's Oncology Group and NRG Oncology.

BACKGROUND AND OBJECTIVES: The impact upon wound healing of targeted molecular therapies, when incorporated into neoadjuvant therapy of soft tissue sarcoma, is largely unknown. Here, we describe wound complications following addition of pazopanib, a tyrosine kinase inhibitor (TKI), to neoadjuvant radiotherapy (RT) +/- chemotherapy for soft tissue sarcoma. METHODS: Wound complications were evaluated on dose-finding and randomized arms of ARST1321, a phase II/III study incorporating neoadjuvant RT, +/- pazopanib, +/- ifosfamide/doxorubicin (ID) for sarcoma therapy. RESULTS: Of 85 evaluable patients, 35 (41%) experienced postoperative wound complications. Most (57%) were grade III. Randomization to pazopanib + RT + ID carried a 50% wound complication rate (17/34, with 47% grade III), compared to 22% (5/23) with ID + RT alone. In nonchemotherapy study arms, pazopanib + RT resulted in a 59% wound complication rate versus 25% for those receiving RT alone. Grade III wound complications occurred among 26% (15/58) of all patients receiving pazopanib. Wound complications occurred a median of 35 days postoperatively. Some occurred following diagnostic biopsies and at remote surgical sites. CONCLUSION: The addition of pazopanib to neoadjuvant chemotherapy and RT resulted in a higher wound complication rate following therapy of soft tissue sarcoma. The rate of grade III complications remained comparable to that reported in contemporary literature.

Children's Oncology Group's 2023 blueprint for research: Soft tissue sarcomas.

In the United States, approximately 850-900 children and adolescents each year are diagnosed with soft tissue sarcomas (STS). STS are divided into rhabdomyosarcoma (RMS) and non-rhabdomyosarcoma STS (NRSTS). RMS and NRSTS are risk stratified into low-, intermediate-, and high-risk categories, with 5-year survival rates of approximately 90%, 50%-70%, and 20%, respectively. Recent key achievements from the Children's Oncology Group (COG) STS Committee include the identification of new molecular prognostic factors for RMS, development and validation of a novel risk stratification system for NRSTS, successful completion of a collaborative NRSTS clinical trial with adult oncology consortia, and collaborative development of the INternational Soft Tissue SaRcoma ConsorTium (INSTRuCT). Current COG trials for RMS are prospectively evaluating a new risk stratification system that incorporates molecular findings, de-intensification of therapy for a very low-risk subgroup, and augmented therapy approaches for intermediate- and high-risk RMS. Trials for NRSTS exploring novel targets and local control modalities are in development.

Feasibility of combining temsirolimus to vincristine, dactinomycin, cyclophosphamide, and vincristine and irinotecan chemotherapy for children with intermediate-risk rhabdomyosarcoma: A report from Children's Oncology Group.

BACKGROUND: Temsirolimus has shown in vivo activity against rhabdomyosarcoma (RMS). We aimed to determine the feasibility of incorporating temsirolimus within the standard Children's Oncology Group (COG) chemotherapy backbone of vincristine, actinomycin-D, and cyclophosphamide (VAC) alternating with vincristine and irinotecan (VI) in children with intermediate-risk (IR) RMS. METHODS: The feasibility phase of the COG IR-RMS trial, ARST1431 (NCT02567435), assigned 10 patients to receive 15 mg/m2 /dose (dose level 1) of temsirolimus on days 1, 8, and 15 of each of three weekly VAC and VI cycles for the first 12 weeks of induction chemotherapy. The primary endpoint of the feasibility phase was to establish the safe dose and safety of combining temsirolimus with VAC/VI. The combination regimen was deemed feasible if less than 40% of patients developed a priori defined nonhematological dose-limiting toxicities (DLTs). RESULTS: Ten patients (seven males and three females; median age = 4.5 years [range: 0.2-14.4 years]) with IR-RMS were enrolled and received dose level 1 of temsirolimus. Eight patients had FOXO1-negative disease, while two had FOXO1-positive disease. Two patients had metastatic disease. Of 10 patients, two developed DLTs: grade 3 oral mucositis and pneumonitis. Four patients (40%) had grade 4 neutropenia. No treatment-related mortality occurred. The median duration of the completion of the feasibility phase was 12.1 weeks (range: 11.7-15 weeks). CONCLUSIONS: Weekly temsirolimus at 15 mg/m2 /dose during VAC/VI chemotherapy was feasible and well tolerated. The efficacy of this regimen is currently being tested in a phase III randomized trial against VAC/VI chemotherapy alone in the ARST1431 trial.

Management and outcomes of chest wall rhabdomyosarcoma: A report from the Children's Oncology Group Soft Tissue Sarcoma Committee.

INTRODUCTION: Rhabdomyosarcoma (RMS) of the chest wall presents unique management challenges and local control considerations. The benefit of complete excision is uncertain and must be weighed against potential surgical morbidity. Our aim was to assess factors, including local control modality, associated with clinical outcomes in children with chest wall RMS. METHODS: Forty-four children with RMS of the chest wall from low-, intermediate-, and high-risk Children's Oncology Group studies were reviewed. Predictors of local failure-free survival (FFS), event-free survival (EFS), and overall survival (OS) were assessed, including clinical characteristics and staging, primary tumor anatomic locations, and local control modalities. Survival was assessed by Kaplan-Meier analysis and the log-rank test. RESULTS: Tumors were localized in 25 (57%) and metastatic in 19 (43%), and they involved the intercostal region (52%) or superficial muscle alone (36%). Clinical group was I (18%), II (14%), III (25%), and IV (43%), and ultimately 19 (43%) patients had surgical resection (upfront or delayed), including 10 R0 resections. Five-year local FFS, EFS, and OS were 72.1%, 49.3%, and 58.5%, respectively. Univariate factors associated with local FFS included age, International Rhabdomyosarcoma Study (IRS) group, extent of surgical excision, tumor size, superficial tumor location, and presence of regional or metastatic disease. Other than tumor size, the same factors were associated with EFS and OS. CONCLUSIONS: Chest wall RMS has variable presentation and outcome. Local control is a significant contributor to EFS and OS. Complete surgical excision, whether upfront or after induction chemotherapy, is usually only possible for smaller tumors confined to the superficial musculature but is associated with improved outcomes. While overall outcomes remain poor for patients with initially metastatic tumors, regardless of local control modality, complete excision may be beneficial for patients with localized tumors if it can be achieved without excess morbidity.

Prognosis of children and young adults with newly diagnosed rhabdomyosarcoma metastatic to bone marrow treated on Children's Oncology Group studies.

BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Metastatic disease occurs in 16% of all RMS cases and has a poor prognosis. There are limited studies examining the outcomes specific to patients with RMS metastatic to bone marrow despite an incidence of 6% at diagnosis. Our study aims to document the outcomes, prognostic factors, and clinical courses of children presenting with RMS metastatic to bone marrow treated on Children's Oncology Group (COG) cooperative trials. METHODS: We performed a retrospective analysis of the patients diagnosed with RMS metastatic to bone marrow between 1997 and 2013 enrolled on one of four COG RMS clinical trials of D9802, D9803, ARST0431, and ARST08P1. RESULTS: We identified 179 cases with RMS metastatic to bone marrow. Patients had a median age of 14.8 years, 58% were male, predominantly alveolar histology (76%), extremity was the most common primary site (32%), and 87% had metastatic disease to additional sites; 83% (n = 149) received radiation as a treatment modality. The 3- and 5-year event-free survival was 9.4% and 8.2%, respectively. The 3- and 5-year overall survival was 26.1% and 12.6%, respectively. Age ≥10 years, alveolar histology, FOXO1 fusion presence, unfavorable primary location, higher Oberlin score, and lack of radiation were identified as poor prognostic/predictive characteristics. CONCLUSIONS: This study represents the largest analysis of RMS metastatic to bone marrow, defining the poor prognostic outcome for these patients. These patients may be eligible for therapy deintensification or early pursuit of novel treatments/approaches that are desperately needed.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

Advances in the clinical management of high-risk Wilms tumors.

Outcomes are excellent for the majority of patients with Wilms tumors (WT). However, there remain WT subgroups for which the survival rate is approximately 50% or lower. Acknowledging that the composition of this high-risk group has changed over time reflecting improvements in therapy, we introduce the authors' view of the historical and current approach to the classification and treatment of high-risk WT. For this review, we consider high-risk WT to include patients with newly diagnosed metastatic blastemal-type or diffuse anaplastic histology, those who relapse after having been initially treated with three or more different chemotherapeutics, or those who relapse more than once. In certain low- or low middle-income settings, socio-economic factors expand the definition of what constitutes a high-risk WT. As conventional therapies are inadequate to cure the majority of high-risk WT patients, advancement of laboratory and early-phase clinical investigations to identify active agents is urgently needed.

Rhabdomyosarcoma with isolated lung metastases: A report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

BACKGROUND: To determine outcomes of children with rhabdomyosarcoma (RMS) with isolated lung metastases. METHODS: Data were analyzed for 428 patients with metastatic RMS treated on COG protocols. Categorical variables were compared using Chi-square or Fisher's exact tests. Event-free survival (EFS) and overall survival (OS) were estimated using Kaplan-Meier method and compared using the log-rank test. RESULTS: Compared with patients with other metastatic sites (n = 373), patients with lung-only metastases (n = 55) were more likely to be <10 years of age, have embryonal histology (embryonal rhabdomyosarcoma), have N0 disease, and less likely to have primary extremity tumors. Lung-only patients had significantly better survival outcomes than patients with all other sites of metastatic disease (p < .0001) with 5-year EFS of 48.1 versus 18.8% and 5-year OS of 64.1 versus 26.9%. Patients with lung-only metastases, and those with a single extrapulmonary site of metastasis, had better survival compared with patients with two or more sites of metastatic disease (p < .0001). In patients with ERMS and lung-only metastases, there was no significant difference in survival between patients ≥10 years and 1-9 years (5-year EFS: 58.3 vs. 68.2%, 5-year OS: 66.7 vs. 67.7%). CONCLUSIONS: With aggressive treatment, patients with ERMS and lung-only metastatic disease have superior EFS and OS compared with patients with other sites of metastatic disease, even when older than 10 years of age. Consideration should be given to including patients ≥10 years with ERMS and lung-only metastases in the same group as those <10 years in future risk stratification algorithms.

TP53 germline pathogenic variant frequency in anaplastic rhabdomyosarcoma: A Children's Oncology Group report.

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni syndrome, resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) are associated with a high rate of germline TP53 PVs. This study provides updated estimates of the prevalence of TP53 germline PVs in RMS (3%) and anRMS (11%) from a large cohort (n = 239) enrolled in five Children's Oncology Group (COG) clinical trials. Although the prevalence of germline TP53 PVs in patients with anRMS in this series is much lower than previously reported, this prevalence remains elevated. Germline evaluation for TP53 PVs should be strongly considered in patients with anRMS.

Patients with completely resected nongenitourinary low-risk embryonal rhabdomyosarcoma are candidates for reduced duration low-intensity chemotherapy.

BACKGROUND: The survival of patients with localized embryonal rhabdomyosarcoma (RMS) completely resected at diagnosis is greater than 90%. Most patients have paratesticular, uterine, or vaginal RMS, limiting specific analyses of RMS localized in other anatomic regions. This international study was conducted to define the outcome for completely resected embryonal RMS at sites other than paratesticular, uterine, or vaginal primary sites. METHODS: A total of 113 patients aged 0-18 years were identified who were enrolled from January 1995 to December 2016 in Children's Oncology Group (COG) (64 patients) and European protocols (49). Genitourinary nonbladder and prostate RMS were excluded. The recommended chemotherapy was vincristine and actinomycin-D (VA) for 24 weeks or ifosfamide plus VA in the European protocols and VA for 48 weeks or VA plus cyclophosphamide in the COG protocols. RESULTS: The most common primary sites were nonparameningeal head and neck (40.7%), other (23.9%), and extremities (20.4%). In the COG studies, 42% of patients received VA and 58% VA plus cyclophosphamide. In Europe, 53% received VA and 47% ifosfamide plus VA. With a median follow-up of 97.5 months, the 5-year progression-free and overall survival was 80.0% (71.2%-86.4%) and 92.5% (85.6%-96.2%), respectively, without significant differences between chemotherapy regimens. Tumor size (< or >5 cm) significantly influenced overall survival: 96.2% (88.6%-98.8%) vs. 80.6% (59.5%-91.4%), respectively (p = .01). CONCLUSIONS: Survival of patients with nonalveolar RMS completely resected at diagnosis is excellent among tumors arising from nonparatesticular, uterine, and vaginal sites, and patients may be treated successfully with low-intensity chemotherapy. To reduce the burden of treatment, VA for 24 weeks may be considered in children with tumors <5 cm.

An update on rhabdomyosarcoma risk stratification and the rationale for current and future Children's Oncology Group clinical trials.

Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous population with variable overall survival rates ranging between approximately 6% and 100% depending on defined risk factors. Although the risk stratification of patients has been refined across five decades of collaborative group studies, molecular prognostic biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in upfront risk-based therapy assignments. This review describes the evolution of risk-based therapy and the current risk stratification, defines a new risk stratification incorporating novel biomarkers, and provides the rationale for the current and upcoming Children's Oncology Group RMS studies.